Abstract
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Alzheimer Disease / drug therapy*
-
Amyloid Precursor Protein Secretases / metabolism*
-
Amyloid beta-Peptides / antagonists & inhibitors
-
Amyloid beta-Peptides / metabolism*
-
Animals
-
Brain / metabolism
-
Bridged Bicyclo Compounds, Heterocyclic / chemistry
-
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
-
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
-
Humans
-
Imines / chemistry*
-
Imines / pharmacokinetics
-
Imines / therapeutic use*
-
Mice
-
Mice, Transgenic
-
Peptide Fragments / antagonists & inhibitors
-
Peptide Fragments / metabolism*
-
Rats
-
Structure-Activity Relationship
Substances
-
Amyloid beta-Peptides
-
Bridged Bicyclo Compounds, Heterocyclic
-
Imines
-
Peptide Fragments
-
amyloid beta-protein (1-42)
-
Amyloid Precursor Protein Secretases